Lymphedema is a lifelong risk. An interview with Dr. Wei Chen of the Cleveland Clinic.

Research Advances

Lymphedema is a lifelong risk

volunteers were tested for the peak or maximal lymphatic pressure they can generate in their lymphatic system and researchers found that this ability to generate pressure declines with age. The earliest drop they identified was in people in their 30s. Then in their fourth and fifth decade, this just continued to drop.

This means that for example, a patient with cervical cancer who underwent a hysterectomy, pelvic lymph node dissection and radiation while in her 30s, had no lymphedema or swelling in her 30s, 40s, or 50s—she may still develop swelling in her 60s.

Do we label that patient as having acquired

Photo: newsroom.clevelandclinic.org

Is lymphedema a lifelong risk for anyone who has had breast cancer, gynecological cancer etc.?

Based on our current understanding, particularly in a field as novel and rapidly advancing such as lymphedema treatment, the short answer is yes, lymphedema is a lifelong risk. Cancer surgery and radiation, or any direct traumatic injury that damages the lymphatic system, are all cumulative injuries that diminish our lymphatic reserve.1 Why? Because lymphatic function, like all bodily function, declines with age. Studies, including one from Japan2 prove this. Healthy

Dr. Wei Chen is a professor of plastic surgery at Cleveland Clinic and serves as the head of microsurgery and super microsurgery and co-director of Cleveland Clinic’s multidisciplinary lymphedema center. He is internationally renowned for his expertise in lymphatic super microsurgery, pioneering several procedures for lymphedema reconstruction.

Dr. Anna Towers runs the lymphedema program at McGill University Health Centre (Montreal, Quebec) and is on the Editorial Board of Pathways.

Anna Kennedy (Toronto, Ontario) is the Editor of Pathways magazine.

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Anna Kennedy and Dr. Anna Towers recently interviewed Dr. Wei Chen, who kindly addressed some patient-related concerns and questions. We appreciate his perspective and enthusiasm to educate patients, therapists and physicians.

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An interview with Dr. Wei Chen of the Cleveland Clinic

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lymphedema (secondary lymphedema) or do we label this as so-called senile lymphedema as a result of progressive decline of lymphatic function with age? Based on our current understanding, it is both. If the patient had not had the cancer operation or radiation treatment, she might have at that age tolerated related decline completely fine and without symptoms, because our bodies have physiological reserve built in. On the other hand, if all she had sustained was cancer treatment-related compromise of lymphatic function, but without the age-related decrease in lymphatic function, she probably wouldn’t have developed lymphedema. So in that situation, based on our current understanding, it’s a mixture of both.

This age-related drop in lymphatic function happens to everyone, even in healthy individuals. We lose bone density, our stamina decreases, our facial skin or collagen decreases, and our metabolism slows down (the list goes on and on). Why would our lymphatic function be any different?

Would you say that this concept applies more to leg lymphedema than arm because of other factors that increase pressure on the legs as people age?

They might have comorbidities such as obesity and varicose veins and just the fact of standing?

Scientifically, we don’t know whether this age related decline is more so in any particular part of the body as this has not been studied. But in terms of the pathogenesis of lymphedema, the legs (compared to say, for example, arms or head and neck) definitely are disadvantaged Ly m p h e d e m a p a t h w a y s . c a 5

What influence does gender have on the lymphatic system?

In the same study2, with a fairly equal distribution of male and female participants, the drop in lymphatic function takes place a lot faster in females. In males, we also saw a drop starting at age 30, but this drop slows down significantly from the fourth decade to the sixth decade. And in females, the two curves become divergent by around age 40. So females continue to drop in almost a linear pattern, whereas the males’ lymphatic function decline slows down. We don’t know whether there are other factors at play, but this is at least one significant factor why we tend to see this female predominance in lymphedema.

Can you explain asymptomatic lymphatic deficiency in layman’s terms?

That’s a very important concept.

There’s a difference between having a detectable lymphatic defect versus having asymptomatic disease. And that’s why I 6 Ly m p h e d e m a p a t h w a y s . c a

That measurement will change depending on whether you measure first thing when the patient gets up, or at the end of the day, and what level of compression the patient is using etc. When did they remove their compression garment before you performed the measurement? Weather and diet etc. also have an impact. So there are too many things that negatively affect volume-based measurement.

But let’s say assuming volume-based measurement is reliable, even so, a key

concept is that swelling is a late symptom.

From the time when the patient developed a detectable lymphatic injury to the time when the patient becomes symptomatic, which has been defined as having swelling, it’s not uncommon that there is a significant lag time.

So the injury has been there for a while and our body starts to try to compensate. We can see that on indocyanine green lymphography.

Our body would sprout all these compensatory pathways, almost similar to peripheral vascular disease when there is a blockage in one of the main arteries, and our body sprouts all this compensatory neovascularization, trying to compensate. We only start to break down with an ulcer in the foot when the body decompensates, when the body has given up, saying, “this is it, this is beyond what I can do.”

The same thing happens with lymphedema.

So when we see swelling, we’ve already lost ground. This underlines the importance of LYMPHA or so-called prophylactic or preventative LVA surgery. Many lymphedema surgeons are objecting to the term prophylactic or preventative because the pathology is already there. It’s just that the patients don’t have symptoms yet; they’re not swollen yet—but that is the best time to intervene. Of course, the success of LYMPHA is dependent on lots of other factors like the experience of surgeons etc. But putting that aside, I think most surgeons would agree that the outcome of LVA at that time point is in general quite favourable

Lymphaticovenular Anastomoses: A) Marking the superficial veins of upper extremity with the Veinsite (VueTek Scientific®, Gray, ME). B) Vein marking with marking pen as viewed through the Veinsite. C) Upper extremity with veins (dotted lines) marked.

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Photo: scitemed.com

because of the legs’ dependent position.

Several other risk factors; weight and coexisting venous insufficiency, are all adverse factors that will further burden or directly injure the lymphatic system. And the effects on the legs are definitely more so compared to other parts of the body, again, because of the legs’ dependent position. So in terms of pathogenesis, I think the legs are hit harder.

But concerning age-related decline, whether it happens more so in the leg, that we don’t know and we can’t say. I would speculate, probably not. There is no reason to think that would be the case, although I think we all know that once the disease conditions are in place, lymphedema is a disease process that progresses and propels itself. I think the leg would advance faster for the reason we’ve just discussed.

Photo: Georgia Research Alliance

This age-related drop in lymphatic function happens to everyone, even in healthy individuals.

always discourage diagnosing lymphedema with circumference measurement or any volume-based measurement. Among volumebased measurements (3D scanning, water displacements, circumference measurements, etc.), the worst is circumference measurement because it has such a high inter and intra– rater error. But even the best volume based measurement, 3D scanning, provides you with only a snapshot of how the patients are doing at the exact time of measurement.

From the time when the patient developed a detectable lymphatic injury to the time when the patient becomes symptomatic, which has been defined as having swelling, it’s not uncommon that there is a significant lag time.

compared to the therapeutic LVA, which when performed properly still has a very favourable outcome as well. Relatively speaking, LYMPHA, which is intervening at a much earlier time point, has a more favourable prognosis.

How is the process of lymphatic insufficiency different in primary versus secondary lymphedema?

There are several differences. The first difference is that in secondary lymphedema, there is no underdevelopment or hypoplasia.

There is a blockage, which based on our current understanding, causes backflow or lymphatic hypertension, similar to that of a garden hose being pinched. The elevated pressure in the “hose”, will in turn damage the lymph channels. And this damage in lymph channels results in loss of this pump function (or the peristalsis of the lymph vessels), and that further builds up a further increase in lymphatic pressure. It’s a vicious cycle. And from that point on, there is progressive loss in the lymphatic pump function causing further damage and pathogenesis.

Whereas in primary lymphedema, there is underdevelopment, with the degree of hypoplasia varying from patient to patient.

Conceptually, you can imagine that someone having 20% of their lymphatic system missing will have disease progression behave very differently compared to someone who has 60% missing. How they would respond to manual lymphatic drainage would also be very different. If you try to perform LVA in the ones with only 20% deficiency (meaning 80% of the lymphatics are developed), it would be

quite easy to find lymphatic vessels. Whereas someone, for example, who has only 10% of the lymphatic system developed has severe hypoplasia, and we’re going to have a very difficult time finding any lymphatic tissues for us to work with.

Another implication is that the current prevalence of asymptomatic primary lymphatic insufficiency is unknown. Most clinicians are unaware of asymptomatic primary lymphatic insufficiency but it is important for them to start recognizing this. How did we initially become aware of this entity? We have patients coming to our clinic with the diagnosis of acquired lymphedema, and when we asked them, “How did you acquire your lymphedema?” patients would say, “I sprained my ankle, and after that I developed lymphedema.”

Or “I developed lymphedema after my knee replacement”. But based on our understanding of lymphatic physiology, we know the lymphatic system is much more robust and such injury would be insufficient for pathogenesis.

Without predisposing conditions and by themselves, those mechanisms are insufficient

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What is the prevalence of primary lymphedema, as you understand it?

We don’t know. Textbooks are saying primary lymphedema is rare, but I can tell you from what I see, it’s not rare. Of course at the Cleveland Clinic I see a selected patient population and, therefore, my practice may not be representative. But in my practice, patients with primary lymphedema Summer 2021

I’ve heard you suggest that traditional classification of primary lymphedema be discarded.

That’s actually my personal opinion and shared by some others. Peter Mortimer’s group in England looks at different classification from a genetic testing standpoint; whether the primary lymphedema is syndromic, whether there is visceral involvement. But that really gets into another big topic. I think in general, they are in agreement with us in that the older classification really carries very little meaning and it reflects our lack of understanding in the past. Whether onset for primary lymphedema is around the age 35, before or after 35... is inconsequential because we are not treating the patient any differently.

While the age 35 specification is inconsequential, the age of onset in. does in fact have r ve de e e .r w meaning.

The timing ww Photo: of swelling has to do with the time when there is an imbalance between lymph production and lymph drainage. This means that if someone develops swelling in her 50s, it tells us that for 50 years, this patient has sufficient lymphatic drainage, compared to another patient who is swollen at birth and therefore already insufficient. How do these two patients compare? The one who was swollen at birth most likely had even less lymphatic function, more severe hypoplasia so that even at birth she had insufficient amount of drainage to meet the need.

Whereas someone who had a much later onset, she is fairly well developed in terms of the lymphatic function. So based on what we have seen, the age of onset does imply severity.

Most clinicians are unaware of asymptomatic primary lymphatic insufficiency but it is important for them to start recognizing this.

Photo: CLF PhotoBank

represent approximately 40% of my patients.

Breast cancer related lymphedema really isn’t the majority. It’s just that the breast cancer patient population in general is a more vocal group, which is a good thing, and they also tend to receive more attention from the media. That unfortunately results in underexposure of other patients.

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to cause lymphedema. So when we hear that history, we should always suspect primary lymphedema. Our subsequent protocol requires that we study all four limbs, both arms and both legs. For a patient who sprained her right ankle and developed right leg lymphedema, we would also study the left leg and both arms. And we consistently found in a patient with that type of history, not only that their right leg has lymphedema, their left leg and both arms were also abnormal, although they were without symptoms. So based on this consistent finding, we drew two conclusions.

First of all, primary lymphedema is a global hypoplasia—there’s no such a thing as primary lymphedema of the right leg. It’s primary lymphedema affecting the patient’s lymphatic system globally. The second conclusion is that now this patient is a “lymphedema time bomb” of her arms and her other leg. If, unfortunately this patient also develops breast cancer and has a sentinel lymph node dissection in which the breast surgeon removes two lymph nodes from say the right armpit, this would have been otherwise well tolerated by someone without this entity. But in this patient, she would develop lymphedema. She would likely be misdiagnosed as acquired (secondary) lymphedema. Why wouldn’t she? She had breast cancer and she had lymph node dissection, and she had radiation. But when in reality this patient had primary lymphedema and she probably would have developed lymphedema in the arm eventually anyway because of the age-related decline.

So how then do you suggest lymphedema be staged?

I tend not to focus too much on staging.

Staging systems were created so lymphedema professionals can communicate more effectively with each other. All staging systems describe the same disease. It’s more important to understand the disease process, the disease progression, the natural history of disease, and the pathogenesis than trying to artificially classify them, which is, in my opinion, missing the point. Instead, understand the disease process and think about how to best help the patient. LP References 1. Q in, Evelyn S., Mindy J. Bowen, and Wei F. Chen. “Is the risk of lymphedema life-long following treatment for gynecologic cancer? A case report.” Current problems in cancer 44.4 (2020): 100538.)

2. Unno, N., et al. “Influence of age and gender on human lymphatic pumping pressure in the leg.” Lymphology 44.3 (2011): 113-120.)

Editor’s Note: The second part of the transcribed interview with Dr. Chen will be featured in the Fall issue of Pathways. That article will focus on surgical perspectives including his LYMPHA surgical technique.

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